PROJECT SUMMARY/ABSTRACT Adolescent human immunodeficiency virus (HIV) and depression present significant public health challenges for South Africa, a country with the largest HIV epidemic globally and where structural factors including vio- lence and poverty increase susceptibility for poor mental health. In families already experiencing psychological distress, adolescents face elevated risk for sexually transmitted infections (STIs) including HIV and depres- sion. Preventive interventions are urgently needed during adolescence when risks for HIV, STIs, and depres- sion in-crease exponentially. Preventive intervention strategies for adolescents should substantively involve families who can tailor prevention content to meet the unique needs of individual adolescents and reinforce formation and habituation of prevention behaviors. Moreover, evidence indicates common family risk and pro- tective factors for adolescent HIV/STI risk behaviors and depression, underscoring the need for a family pre- vention approach. However, key gaps exist in family prevention science. In South Africa, few empirically sup- ported family interventions integrate prevention of HIV/STI with depression for adolescents. Our resilience-ori- ented approach engages families in adolescent prevention from low-resource settings facing high adversity. We focus on adolescents (14-16 years of age) who are at an ideal developmental transition for family engage- ment in prevention. Our age- and developmentally-tailored intervention ? called Our Family Our Future ? is based off of two empirically supported interventions that have been integrated and adapted to South Africa. In a pilot randomized trial, Our Family Our Future exhibited outstanding acceptability, feasibility and promising direction of effects including reductions of depressive symptoms; lower rates of sex; decreased unprotected sex; increased HIV testing; increased knowledge, motivation, intentions and self-efficacy for protective HIV/STI behaviors; improved family interactions; and increased resilience. Now we propose the next phase of this re- search program, an efficacy study of Our Family Our Future with three aims: (1) test the efficacy of the Our Family Our Future intervention in preventing HIV/STI acquisition among adolescents (14-16 years of age) with depressive symptoms by reducing HIV/STI risk behavior, and reducing depressive symptoms. The project will randomize N=880 adolescents to Our Family Our Future intervention or usual care with 6- and 12-month out- come assessments; (2) examine the extent to which the impact of the Our Family Our Future intervention is a) mediated by changes in resilience; behavioral skills; norms and attitudes relating to sex, condom use, gender; and family communication and functioning and b) moderated by the effect of sociodemographics, family HIV, and social protections; (3) identify barriers and facilitators to implementing Our Family Our Future within a large community-based organization setting with wide reach to provide data for future dissemination and scale-up. The study fills a significant gap in family prevention science in a priority population and setting and is aligned with the Trans-NIH Plan for HIV, NIMH, NIAID, and NICHD strategic research priorities.